IE56610B1 - Triazole antifungal agents - Google Patents

Triazole antifungal agents

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Publication number
IE56610B1
IE56610B1 IE175/84A IE17584A IE56610B1 IE 56610 B1 IE56610 B1 IE 56610B1 IE 175/84 A IE175/84 A IE 175/84A IE 17584 A IE17584 A IE 17584A IE 56610 B1 IE56610 B1 IE 56610B1
Authority
IE
Ireland
Prior art keywords
compound
formula
acceptable salt
agriculturally acceptable
pharmaceutically
Prior art date
Application number
IE175/84A
Other versions
IE840175L (en
Original Assignee
Pfizer Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Pfizer Ltd filed Critical Pfizer Ltd
Publication of IE840175L publication Critical patent/IE840175L/en
Publication of IE56610B1 publication Critical patent/IE56610B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Dentistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Plant Pathology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Triazoles of the formula: <CHEM> and their pharmaceutically and agriculturally acceptable salts, wherein m is 0, 1, 2, 3 or 4 and n is 0, 1, 2, 3 or 4. The compounds are human and agricultural fungicides.

Description

This Invention relates eo novel tuia^ole derivatives which < have antifungal activity and ate useful ia the treatment of fungal infections in animalsP including humansp and as plant fungicides.
Triazole derivatives having fungicidal activity are already known from the prior art, see for example EP-A-52424 and US-A-4243405.
According to the Invention, there are provided compounds of the formula:- where m Is 0, 1, 2, 3 or 4; and n is 1, 2, 3 or 4; and their pharmaceutically and agriculturally acceptable salts.
The invention also provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
The invention further provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use in medicine, in particular for treating fungal infections in animals, including humans. ' The Invention yet further provides a composition for use as an agricultural (Including horticultural) fungicide, comprising a compound of the formula (1) or an agriculturally acceptable salt thereof, together tilth an agriculturally acceptable diluent or carrier. - 3 ί> I Preferably, m is 0 or 1 and n is 1, 2 or 3.
The compounds of the formula.(I) can be prepared as follows:OH Q*CH.-C-(CF.)-CF. 2 ι 2 m J ^(preferably ln the presence of a base such as K^CO^) CH (CF ) -CF. 2 m j (CF.,>n j 2 n (CF2) 1 CF. or 1 CF. 3 (II) 3 (I) where Q Is a leaving group such as Cl, Br, I, CF^SO^O-jCH^SOjO- or 10 j£-toluenesulphonyloxy, and M Is preferably Na, K or Li.
In a typical procedure, 1,2,4-trlazole, the starting material (11) and potassium carbonate are heated together at, say, 50-130eC, In a suitable organic solvent, e.g. dimethylformamide, until the reaction Is complete. The product (I) can then be isolated and purified In a conventional manner.
The starting materials of the formula (II) can be obtained in a conventional manner, e.g. - 4 cF3(CF2)nMgI or CF3(CF2)nMsBr v Q.CH*CO(CF,) CF, -> Compound (II). ί ί ® (III) Q le preferably Br. The starting materials of the formula (III) are either known compounds or can be obtained conventionally, e.g. CF,(CF9) COCH, J i. m J Br, ^CF3(CF2)iBCOCH2Br (see JACS, 78, 2268-70 [1956]).
Where the compounds of the fonnula (I) contain an optically active centre the Invention Includes both the resolved and unresolved forms.
Pharmaceutically acceptable acid addition salts of the compounds of the formula (I) are those formed from strong acids which form non-toxic add addition salts, such as hydrochloric, hydrobromlc, sulphuric, oxalic and methanesulphonlc acids.
The salts may be obtained by conventional procedures, e.g, by mixing solutions containing equimolar amounts of the free base and desired acid, and the required salt Is collected hy filtration, If insoluble, or by evaporation of the solvent. - 5 The compounds of the formula (I) and their pharmaceutically acceptable salts are antifungal agents, useful In combating fungal Infections in animals, including humans. For example they are useful In treating topical fungal infections in man caused by, among other organisms, species of Candida, Trichophyton, Microsporum or Epldermophyton, or in mucosal Infections caused by Candida albicans (e.g. thrush and vaginal candidiasis). They can also be used In the treatment of systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccldloldes, Paracoccidioides, Hlstoplasma or Blastomyces.
The in vitro evaluation of the antifungal activity of the compounds can be performed by determining the minimum Inhibitory concentration (m.l.c.) of the test compounds in a suitable medium at which growth of the particular micro-organism falls to occur.
In practice, a series of agar plates, each having the test compound Incorporated at a particular concentration is Inoculated with a standard culture of, for example, Candida albicans and each plate is then incubated for 48 hours at 37°C. The plates are then examined for the presence or absence of growth of che fungus and the appropriate m.l.c. value Is noted. Other micrororganlsms used in such tests can Include Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spp; Microsporum spp; Epldermophyton floccosum, Coccldloldes immitis and Torulopsis glabrata.
I - 6 The In vivo evaluation of the compounds can be carried out at a series of dose levels by Intraperitoneal or Intravenous Injection or by oral administration, to mice which are Inoculated with a strain of Candida albicans. Activity is based on the survival of a treated group of mice after the death of an untreated group of mice following 48 hours observation. The dose level at which the compound provides 50% protection against the lethal effect of the infection (PD^q) Is noted.
For human use, the antifungal compounds of the formula (I) can he administered alone, but will generally be administered In admixture with a pharmaceutical carrier selected with regard to the Intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or In admixture with excipients, or In the form of elixirs or suspensions containing flavouring or colouring agents. They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used In the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution Isotonic with blood.
For oral and parenteral administration to human patients, the dally dosage level of the antifungal compounds of the formula (1) will be from 0.1 to 10 mg/kg (in divided doses) when administered by either the oral or parenteral route. Thus tablets or capsules of the compounds will contain from 5 mg to 0.5 g of active - 7 compound for administration singly or two or more at a time as appropriate. The physician In any event will determine the actual dosage which will be most suitable for an Individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual Instances where higher or lower dosage ranges are merited, and such are within the scope of this Invention.
Alternatively, the antifungal compounds of formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically ln the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be Incorporated, at a concentration between 1 and 10Z, Into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
The compounds of the formula (I) and their salts also have activity against a variety of plant pathogenic fungi, including for example various rusts, mildews and moulds, and the compounds are thus useful for treating plants and seeds to eradicate or prevent such diseases. i - 8 The in vitro evaluation of the activity of the compounds against plant fungi can be determined by measuring their minimum inhibitory concentrations in the same way as previously described except that the plates are Incubated at 30°C for 48 hours or t longer before being examined for the presence or absence of growth. I.
Micro-organisms used in such tests include Cochliobolus carbonum, Pyrlcularla oryzae, Glomerella cingulata, Penicillium digitatum, Botrytis cinerea and Rhizoctonia solan!.
For agricultural and horticultural purposes the compounds and their agriculturally acceptable salts are preferably used in the form of a composition formulated as appropriate to the particular use and purpose desired. Thus the compounds may be applied In the form of dusting powders, or granules, seed dressings, aqueous solutions, dispersions or emulsions, dips, sprays, aerosols or smokes. Compositions may also be supplied in the form of dispersible powders, granules or grains, or concentrates for dilution prior to use. Such compositions may contain such conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture and they are manufactured In accordance with conventional procedures. The compositions may also incorporate other active Ingredients, for example, compounds having herhlcldal or Insecticidal activity or a further fungicide. The compounds and compositions can be applied In a number of ways, for example they can be applied directly to the plant foliage, stems, branches, seeds or roots or to the soil - 9 The following Examples illustrate the Invention. All tetaperaturss are In ’CiOH BrCH2CCF3 2)2 CF.
EXAMPLE 1 Preparation of decaflupro-2-(lH-l,2,4-trlazol-l-ylmethyl)pentan5 2^ol 1) PhMgBr CF3CF2CF2I 11) BrCH^COCFj_ ill) H® y^H OH -«V/HCH25CF3 K2CO3, DMF (CF2)2 cf3 this reaction were carried out under nitrogen.
(A) Heptafluoropropyl Iodide (5 g) wae stirred in dry diethyl 10 ether (20 ml) at -78°. PhenyImagneslum bromide (10 ml. of a 1.88 M solution In ether) was then added dropwlse, keeping the temperature below -65°. When the addition was complete, the reaction mixture was stirred at -20° for 1 hour. It was then cooled to *78° and 3-bromo-1,1,1- trifluoropropanone (4.87 g) in dry diethylether (20 ol) was added dropwlse, keeping the All stages of t - 10 temperature below -65°. When the addition wae complete, the mixture was' stirred at between -20° and -50° for four hours.
Glacial acetic acid (3 ml) In diethyl ether (5 ml) was then added slowly, followed by water (15 ml). The mixture was then allowed to warm to 5° and the phases were separated. The aqueous phase vas washed with ether (2 x 25 ml). The ethereal extracts were I combined, dried (KgSO^) and evaporated to give crude 2-bromomethyl-decafluoropentan-2-ol (5.0 g).
(B) The crude pentanol from part (A) [5.0 g] was combined with 1,2,4-triazole (6 g), anhydrous potassium carbonate (18 g) and dry dimethylformamide (DMF) (60 ml), and the mixture was heated with stirring at 80° overnight. The DMF vas then removed and water (100 ml) and ethyl acetate (75 ml) were added to the residue. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 75 ml). The ethyl acetate extracts were combined, washed with water (100 ml), dried (MgSO^) and evaporated. Purification of the residue by flash chromatography on silica (230-400 mesh) eluting with, firstly methylene chlorlde/methanol/ammonla (93:7:1 by volume) and secondly with ethyl acetate/hexane (7:1 hy volume) gave, after trituration with hexane, the title compound. This was recrystallized from a mixture of methylene chloride and hexane to give 130 mg of the pure product, melting point 99-101°.
Analysis Found: C.27,9; N.l-4; N,12.1; Calculated for ΟθΗ^^θΟ: C.27.5; H.1.4; N.12.0.
EXAMPLES 2 TO 5 J 5 The following compounds were prepared similarly to the procedure of Example 1(A) and (B) from appropriate starting materials with the differences noted below:OH 1 \=N (CF2)n Example No. m n m.p. (°C) Analysis % (calculated In brackets) C H N 2 0 3 gum 27.4 (27.1 1.4 1.3 10.7 10.5) 3 1 3 62-63 27.3 (26.7 1.2 1.1 9.3 9.4) 4 1 1 67-71 27.6 (27.5 1.5 1.4 11.9 12.0) 5 1 2 67-70 ί 27.0 (27.1 1.2 1.3 10.4 10.5) 1 In examples 2 and 3, the reectlon mixture In part (A) was quenched with 30a aqueous ammonium chloride solution In place of glacial acetic acld/ether/water, and in Examples 4 and 5, 30a aqueous ammonium chloride was used. In Examples 3 and 5 part (A), + methylmagneslum bromide was used In place of phenylmagneslum bromide. Also, In part (A) of all the Examples, the teoq>erature ( of the reaction mixture after the addition of the bromoketone was maintained at -30° Instead of between -20 and -50*. ?1>5θ values for the compounds (oral, mice) In mg./kg. against 1C C. albicans obtained hy the test method described In the text are given below:Product of Example Ro, ΡΡ^θ (mg./kg.)

Claims (6)

CLAIMS 1. Or a pharmaceutically or agriculturally acceptable salt thereof, whenever prepared by a process claimed in claim 11. 13. A pharmaceutical composition according to claim 3, substantially as hereinbefore described. - 15 14. Ά fungicidal composition according to claim 4, substantially as hereinbefore described· 15. A method according to claim 6 of treating a plant or seed having a fungal infection, substantially as hereinbefore
1. ' A compound of the formula:OH Ν’^^Ν-ΟΗ,-Ο- (cf,) -cf, Ζ ι 2 0 3 (I) Wn CF. or a pharmaceutically or agriculturally acceptable salt thereof, 5 wherein m Is 0, 1, 2, 3 or 4; and n is 1, 2, 3 or 4 .
2. · A compound as claimed in claim 1, wherein m is 0 or 1 and n is 1, 2 or 3.
3. A pharmaceutical composition comprising a compound of 10 the formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
4. A fungicidal composition for agricultural (including horticultural) use, comprising a compound of the formula (1) as 15 claimed In claim 1 or 2 or an agriculturally acceptable salt thereof, together with an agriculturally acceptable diluent or carrier. 5. A compound of the formula (I) as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, for uee in 20 medicine, in particular for treating a fungal infection ih a human being. - 14 6. A method of treating a plant or seed having a fungal Infection, which comprises contacting said plant or seed, or the locus of said plant, with an antlfungally effective amount of a compound of the formula (I) as claimed ln claim 1 or 2, or with an 5 agriculturally acceptable salt thereof. 7, A compound of the formula:- t q - α, 2 - c -(¾ - cf 3 (CF,). — (II) I CF. where zn and n are as defined in claim 1 and Q is a leaving group. 10 8. A ctanpound as claimed in claim 7 wherein Q is Cl, Br, l, CF 3 SO 2 <>“r CH^SC^O- or o-toluenesulphonyloxy. 9. A compound as claimed ln claim 8 wherein Q is Br, 10. A compound of the formula (I) given and defined in claim 1 or a pharmaceutically or agriculturally acceptable salt thereof, 15 substantially as hereinbefore described and exemplified. 11. A process for the preparation of a compound of the fornula (I) given and defined ln claim 1 or a pharmaceutically or agriculturally acceptable salt thereof, substantially as hereinbefore described and exemplified. 20 12. A compound of the formula (I) given and defined ln claim
5. Described. J 1
6. A canpound of the formula (II) given and defined in claim 7, substantially as hereinbefore described and exemplified.
IE175/84A 1983-01-29 1984-01-26 Triazole antifungal agents IE56610B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB838302498A GB8302498D0 (en) 1983-01-29 1983-01-29 Antifungal agents

Publications (2)

Publication Number Publication Date
IE840175L IE840175L (en) 1984-07-29
IE56610B1 true IE56610B1 (en) 1991-10-09

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ID=10537165

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IE175/84A IE56610B1 (en) 1983-01-29 1984-01-26 Triazole antifungal agents

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US (1) US4483862A (en)
EP (1) EP0115939B1 (en)
JP (1) JPS59172480A (en)
KR (1) KR870000786B1 (en)
AT (1) ATE36527T1 (en)
AU (1) AU542435B2 (en)
CA (1) CA1247629A (en)
DE (1) DE3473447D1 (en)
DK (1) DK161517C (en)
ES (1) ES8504432A1 (en)
FI (1) FI85695C (en)
GB (1) GB8302498D0 (en)
GR (1) GR81666B (en)
HU (1) HU193279B (en)
IE (1) IE56610B1 (en)
IL (1) IL70796A (en)
PH (1) PH18933A (en)
PL (1) PL143855B1 (en)
PT (1) PT78015B (en)
YU (1) YU13584A (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02145524A (en) * 1988-11-29 1990-06-05 Katsumi Nagata Production of raw material of drug obtained from pyroligneous acid
DE4030061A1 (en) * 1990-06-13 1991-12-19 Bayer Ag Prepn. of benzyl ketone derivs. for fungicidal intermediates - by reacting benzyl chloride derivs. with zinc powder, removing excess zinc and reacting prod. with acid chloride
US5194636A (en) * 1990-06-13 1993-03-16 Bayer Aktiengesellschaft Preparation of benzyl ketones and an oxirane
DE4025204A1 (en) * 1990-08-09 1992-02-13 Bayer Ag HALOGENALKYL-AZOLYL DERIVATIVES

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Publication number Priority date Publication date Assignee Title
DE2431407C2 (en) * 1974-06-29 1982-12-02 Bayer Ag, 5090 Leverkusen 1,2,4-Triazol-1-yl-alkanones and alkanols, processes for their preparation and their use as fungicides
IE45765B1 (en) * 1976-08-19 1982-11-17 Ici Ltd Triazoles and imidazoles useful as plant fungicides and growth regulating agents
EP0158741A3 (en) * 1980-11-19 1986-02-12 Imperial Chemical Industries Plc Intermediates for fungicidal triazole and imidazole compounds
US4616027A (en) * 1982-08-14 1986-10-07 Pfizer Inc. Antifungal 1-aryl-1-fluoroalkyl-2-(1H-1,2,4-triazol-1-yl)ethanols

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Publication number Publication date
KR840007588A (en) 1984-12-08
IL70796A (en) 1987-07-31
FI840352A (en) 1984-07-30
EP0115939A2 (en) 1984-08-15
GB8302498D0 (en) 1983-03-02
IE840175L (en) 1984-07-29
GR81666B (en) 1984-12-12
PH18933A (en) 1985-11-11
YU13584A (en) 1986-06-30
JPS6346073B2 (en) 1988-09-13
AU2385684A (en) 1984-08-02
DK161517B (en) 1991-07-15
ES529251A0 (en) 1985-05-01
AU542435B2 (en) 1985-02-21
EP0115939B1 (en) 1988-08-17
PT78015A (en) 1984-02-01
DK38384D0 (en) 1984-01-27
PL245929A1 (en) 1984-11-08
FI85695C (en) 1992-05-25
DK38384A (en) 1984-07-30
US4483862A (en) 1984-11-20
ATE36527T1 (en) 1988-09-15
PL143855B1 (en) 1988-03-31
DK161517C (en) 1992-01-06
FI840352A0 (en) 1984-01-27
JPS59172480A (en) 1984-09-29
IL70796A0 (en) 1984-04-30
KR870000786B1 (en) 1987-04-18
CA1247629A (en) 1988-12-28
HU193279B (en) 1987-09-28
DE3473447D1 (en) 1988-09-22
EP0115939A3 (en) 1986-03-19
FI85695B (en) 1992-02-14
ES8504432A1 (en) 1985-05-01
PT78015B (en) 1986-06-18

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